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The Journal of Veterinary Medical... Mar 2021A 5-year-old castrated male domestic shorthair cat was diagnosed with diabetic ketoacidosis and severe insulin resistance. Although the conventional treatment for...
A 5-year-old castrated male domestic shorthair cat was diagnosed with diabetic ketoacidosis and severe insulin resistance. Although the conventional treatment for diabetic ketoacidosis was provided, the cat required frequent hospitalization because of severe dehydration and repeated diabetic ketoacidosis. We detected anti-insulin antibodies for human in this cat. Serum insulin-binding IgG levels were markedly elevated compared with those in healthy cats and other diabetic cats. We initiated prednisolone to suppress the effects of anti-insulin antibodies. After initiation of prednisolone, the cat was gradually recovered with increasing activity and appetite. Furthermore, satisfactory glycemic control was achieved with combined subcutaneous injection of insulin detemir and insulin degludec.
PubMed: 33678733
DOI: 10.1292/jvms.2-0345 -
ACS Omega Apr 2023Commercially available insulins are manufactured by recombinant methods for the treatment of diabetes. Long-acting insulin drugs (e.g., detemir and degludec) are...
Commercially available insulins are manufactured by recombinant methods for the treatment of diabetes. Long-acting insulin drugs (e.g., detemir and degludec) are obtained by fatty acid conjugation at LysB29 ε-amine of insulin via acid-amide coupling. There are three amine groups in insulin, and they all react with fatty acids in alkaline conditions. Due to the lack of selectivity, such conjugation reactions produce non-desired byproducts. We designed and chemically synthesized a novel thiol-insulin scaffold (CysB-insulin ), by replacing the Lys residue in insulin with the Cys residue. Then, we conjugated a fatty acid moiety (palmitic acid, C16) to CysB-insulin by a highly efficient and selective thiol-maleimide conjugation reaction. We obtained the target peptide (palmitoyl-insulin) rapidly within 5 min without significant byproducts. The palmitoyl-insulin is shown to be structurally similar to insulin and biologically active both in vitro and in vivo. Importantly, unlike native insulin, palmitoyl-insulin is slow and long-acting.
PubMed: 37091377
DOI: 10.1021/acsomega.2c07918 -
Clinical Therapeutics Nov 2022The goal of this study was to compare the efficacy and tolerability of insulin degludec with those of other long-acting insulin analogues (insulin glargine and insulin... (Meta-Analysis)
Meta-Analysis
Efficacy and Tolerability of Insulin Degludec Versus Other Long-acting Basal Insulin Analogues in the Treatment of Type 1 and Type 2 Diabetes Mellitus: A Systematic Review and Meta-analysis.
PURPOSE
The goal of this study was to compare the efficacy and tolerability of insulin degludec with those of other long-acting insulin analogues (insulin glargine and insulin detemir) in patients with type 1 or 2 diabetes mellitus (T1D or T2D).
METHODS
Those randomized controlled trials comparing insulin degludec with other long-acting insulin analogues in the treatment of patients with T1D or T2D published on or before August 21, 2022, were retrieved from PubMed, Web of Science, the Cochrane Library, and EMBASE. The efficacy end points were the changes from baseline in hemoglobin A and fasting plasma glucose (FPG). The tolerability end point was the prevalence of hypoglycemia confirmed throughout the treatment period.
FINDINGS
Data from a total of 20 trials (19,048 patients) were included. The differences in the reductions in glycosylated hemoglobin between insulin degludec and other long-acting basal insulin analogues (insulin glargine and insulin detemir) used for the treatment of patients with T1D or T2D were not significant. However, the reduction in FPG was greater with insulin degludec (-0.370 mmol/L; 95% CI, -0.473 to -0.267 mmol/L; P ≤ 0.001). Throughout the treatment periods of all of the available trials, the estimated rate ratios of overall and nocturnal hypoglycemia were significantly decreased with insulin degludec compared with insulin glargine or insulin detemir in patients with T1D or T2D; the differences in the risks for severe hypoglycemia were not significant.
IMPLICATIONS
Compared with other long-acting insulin analogues (insulin glargine and insulin detemir), insulin degludec was associated with a significantly decreased FPG, with lower prevalences of overall and nocturnal hypoglycemia.
Topics: Humans; Diabetes Mellitus, Type 2; Insulin Glargine; Insulin Detemir; Diabetes Mellitus, Type 1; Hypoglycemic Agents; Insulin, Long-Acting; Hypoglycemia; Glycated Hemoglobin; Blood Glucose
PubMed: 36763996
DOI: 10.1016/j.clinthera.2022.09.012 -
Acta Pharmaceutica Sinica. B Sep 2021Insulin derivatives such as insulin detemir and insulin degludec are U.S. Food and Drug Administration (FDA)-approved long-acting insulin currently used by millions of...
Insulin derivatives such as insulin detemir and insulin degludec are U.S. Food and Drug Administration (FDA)-approved long-acting insulin currently used by millions of people with diabetes. These derivatives are modified in C-terminal B29 lysine to retain insulin bioactivity. New and efficient methods for facile synthesis of insulin derivatives may lead to new discovery of therapeutic insulin. Herein, we report a new method using sortase A (SrtA)-mediated ligation for the synthesis of insulin derivatives with high efficiency and functional group tolerance in the C-terminal B chain. This new insulin molecule (Ins-SA) with an SrtA-recognizing motif can be conjugated to diverse groups with N-terminal oligoglycines to generate new insulin derivatives. We further demonstrated that a new insulin derivative synthesized by this SrtA-mediated ligation shows strong cellular and bioactivity. This enzymatic method can therefore be used for future insulin design and development.
PubMed: 34589392
DOI: 10.1016/j.apsb.2020.11.011 -
Diabetes Therapy : Research, Treatment... Aug 2019The past three decades have seen a quadruple rise in the number of people affected by diabetes mellitus worldwide, with the disease being the ninth major cause of... (Review)
Review
The past three decades have seen a quadruple rise in the number of people affected by diabetes mellitus worldwide, with the disease being the ninth major cause of mortality. Type 2 diabetes mellitus (T2DM) often remains undiagnosed for several years due to its asymptomatic nature during the initial stages. In India, 70% of diagnosed diabetes cases remain uncontrolled. Current guidelines endorse the initiation of insulin early in the course of the disease, specifically in patients with HbA1c > 10%, as the use of oral agents alone is unlikely to achieve glycemic targets. Early insulin initiation and optimization of glycemic control using insulin titration algorithms and patient empowerment can facilitate the effective management of uncontrolled diabetes. Early glucose control has sustained benefits in people with diabetes. However, insulin initiation, dose adjustment, and the need to repeatedly assess blood glucose levels are often perplexing for both physicians and patients, and there are misconceptions and concerns regarding its use. Hence, an early transition to insulin and ideal intensification of treatment may aid in delaying the onset of diabetes complications. This opinion statement was formulated by an expert panel on the basis of existing guidelines, clinical experience, and economic and cultural contexts. The statement stresses the timely and appropriate use of basal insulin in T2DM. It focuses on the seven vital Ts-treatment initiation, timing of administration, transportation and storage, technique of administration, targets for titration, tablets, and tools for monitoring.Funding: Sanofi.
PubMed: 31102253
DOI: 10.1007/s13300-019-0629-z -
Iranian Journal of Pharmaceutical... 2021The aim of this study was to compare the insulin glargine and detemir effects on hormons affecting appetite and metabolic control of patients with type 1 diabetes. This...
The aim of this study was to compare the insulin glargine and detemir effects on hormons affecting appetite and metabolic control of patients with type 1 diabetes. This single-blind randomized clinical trial was conducted on patients aged 2 to 18 years with type 1 diabetes who were referred to the endocrinology department of Ali-Asghar Children Hospital in Tehran, from April to September 2019. Patients were randomly allocated to receive insulin Glargine or insulin Detemir. Before starting treatment, blood samples were obtained for routine biochemical tests and factors affecting appetite, including Leptin, Ghrelin, Aguti-Related Peptide (AGRP), and Peptide-YY3-36 (PYY 3-36). Patients were evaluated monthly and insulin dose was adjusted based on target glucose and carbohydrate counting. At the end of three months, the anthropometric values , HbA1C and factors that influence appetite were measured again in both groups, and the results were compared. A total of 40 children with a new onset of type 1 diabetes under 18 years who were hospitalized in Ali Asghar Children Hospital were randomly assigned into two groups as Glargine (n = 20) and Detemir (n = 20). The mean age of patients in the Glargine group was 11.07 ±4.18 years and in the Detemir group was 8.06 ± 3.56. In Glargine group HbA1C, Cholesterol, LDL, AGRP significantly decreased and leptin increased after treatment., while the change of BMI Z-score was not significant. There was a significant decrease of HbA1C in the Detemir group after treatment but there was no significant change of other variables. There was no significant difference for all the variables between two groups after treatment. There was no significant difference for BMI, metabolic control and appetite hormones between Glargine and Detemir groups. BMI-z score did not change in Glargine group while leptin increased and AGRP decreased after treatment. HbA1C decreased significantly after treatment in both groups.
PubMed: 34904015
DOI: 10.22037/ijpr.2021.114841.15059 -
Diabetes, Obesity & Metabolism Aug 2021Evidence from randomized controlled trials (RCTs) has shown that second-generation basal insulin (BI) analogues, insulin glargine 300 U/mL (Gla-300) and insulin... (Review)
Review
Evidence from randomized controlled trials (RCTs) has shown that second-generation basal insulin (BI) analogues, insulin glargine 300 U/mL (Gla-300) and insulin degludec (IDeg), provide similar glycaemic control, with a lower risk of hypoglycaemia compared with the first-generation BI analogue insulin glargine 100 U/mL (Gla-100) in people with type 2 diabetes (T2D). However, the highly selected participants and frequent follow-up of RCTs may not be truly representative of real-life clinical practice. It is important to assess the safety and effectiveness of these second-generation BI analogues in real-life clinical practice settings. The DELIVER programme utilized electronic healthcare records from the United States to compare clinical outcomes in people with T2D who received either Gla-300 or other BI analogues in real-world clinical practice. This review provides a concise overview of the results of the DELIVER studies. Overall, Gla-300 provided similar antihyperglycaemic effectiveness and a lower risk of hypoglycaemia versus the first-generation BI analogues Gla-100 and insulin detemir in people with T2D who had switched BIs. In those who were insulin-naïve, initiation with Gla-300 versus Gla-100 was associated with significantly better antihyperglycaemic effectiveness and similar or lower hypoglycaemic risk. Both glycaemic control and hypoglycaemia risk were also shown to be similar with Gla-300 and IDeg, in people who had switched BIs and in those who were insulin-naïve. In addition, the DELIVER 2 study reported that people with T2D who switched to Gla-300 had reduced healthcare resource utilization, with an overall saving of US$1439 per person per year compared with those who switched to another BI analogue. Overall, the real-world DELIVER programme showed that the glycaemic control with a low risk of hypoglycaemia observed with Gla-300 in RCTs was also seen in standard clinical practice.
Topics: Diabetes Mellitus, Type 2; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin Glargine
PubMed: 33881797
DOI: 10.1111/dom.14405 -
Frontiers in Pharmacology 2023Type 1 diabetes is characterized by insulin deficiency, and treatment is to supply insulin mimicking the physiological endogenous insulin secretion. Since its discovery,... (Review)
Review
Type 1 diabetes is characterized by insulin deficiency, and treatment is to supply insulin mimicking the physiological endogenous insulin secretion. Since its discovery, insulin therapy has evolved, and since the 1990s, an increasing number of insulin analogs with various pharmacokinetic and pharmacodynamic profiles have become available. Despite the improvement of insulin therapy, hypoglycemia remains the main side effect and is a daily concern for many people with diabetes and their families. A proportion of people with type 1 diabetes are at increased risk of hypoglycemia and experience recurring episodes. When designing insulin trials, this group of people is most often excluded in order to reduce the risk of adverse study outcomes, even though it may be the group that may benefit the most from treatment with new insulins. The results of the phase III trials, therefore, underestimate the clinical impact and pharmacoeconomic effect of the implementation of new insulins in the broader type 1 diabetes population. This paper reviews the four insulin trials that include people at increased risk of hypoglycemia. In general, the studies confirm the results from phase III trials in terms of similar reduction and maintenance of HbA1c, as well as relative rate reductions of hypoglycemia. However, the absolute treatment differences in the reduction of hypoglycemia are even greater in the trials, including people at high risk of hypoglycemia. This emphasizes the importance of including people at high risk of hypoglycemia to assess the full clinical and pharmacoeconomic benefit of new insulins.
PubMed: 38089060
DOI: 10.3389/fphar.2023.1301931 -
Diabetes Therapy : Research, Treatment... Jan 2021The ongoing global pandemic of the coronavirus disease 2019 (COVID-19) has placed a severe strain on the management of chronic conditions like diabetes. Optimal glycemic... (Review)
Review
The ongoing global pandemic of the coronavirus disease 2019 (COVID-19) has placed a severe strain on the management of chronic conditions like diabetes. Optimal glycemic control is always important, but more so in the existing environment of COVID-19. In this context, timely insulinization to achieve optimal glycemic control assumes major significance. However, given the challenges associated with the pandemic like restrictions of movement and access to healthcare resources, a simple and easy way to initiate and optimize insulin therapy in people with uncontrolled diabetes is required. With this premise, a group of clinical experts comprising diabetologists and endocrinologists from India discussed the challenges and potential solutions for insulin initiation, titration, and optimization in type 2 diabetes mellitus (T2DM) during the COVID-19 pandemic and how basal insulin can be a good option in this situation owing to its unique set of advantages like lower risk of hypoglycemia, ease of training, need for less monitoring, better adherence, flexibility of using oral antidiabetic drugs, and improved quality of life compared to other insulin regimens. The panel agreed that the existing challenges should not be a reason to delay insulin initiation in people with uncontrolled T2DM and provided recommendations, which included potential solutions for initiating insulin in the absence or restriction of in-person consultations; the dose of insulin at initiation; the type of insulin preferred for simplified regimen and best practices for optimal titration to achieve glycemic targets during the pandemic. Practical and easily implementable tips for patients and involvement of stakeholders (caregivers and healthcare providers) to facilitate insulin acceptance were also outlined by the expert panel. Simplified and convenient insulin regimens like basal insulin analogues are advised during and following the pandemic in order to achieve glycemic control in people with uncontrolled T2DM.
PubMed: 33314000
DOI: 10.1007/s13300-020-00979-8